This invention relates to processes for preparing isothiazole derivatives that are useful in the treatment of hyperproliferative diseases, such as cancers, in mammals. It is known that polypeptide growth factors, such as vascular endothelial growth factor (VEGF), which has a high affinity for the human kinase insert-domain-containing receptor (KDR) or the murine fetal liver kinase 1 (FLK-1) receptor, have been associated with the proliferation of endothelial cells and more particularly to vasculogenesis and angiogenesis. The present invention provides a process for preparing compounds that are capable of binding to or modulating the KDR/FLK-1 receptor. The compounds may be used to treat disorders related to vasculogenesis or angiogenesis such as diabetes, diabetic retinopathy, hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast, lung, pancreatic, prostate, colon and epidermoid cancer.
This invention also relates to processes for preparing intermediates that may be converted to the aforementioned isothiazole derivatives and to the intermediates prepared. Processes for preparing isothiazole derivatives and their intermediates have been disclosed in International Patent Publication WO 99/62890, published Dec. 9, 1999, and U.S. Pat. Nos. 6,235,764; 6,380,214; and 6,548,526, issuing on May 22, 2001, Apr. 30, 2002 and Apr. 15, 2003, respectively. Processes for preparing 3-alkoxyisothiazole derivatives as herbicides have been disclosed in U.S. Pat. No. 4,059,433, issuing on Nov. 22, 1977. Processes for preparing 5-amino-3-hydroxy(alkoxy,-amino-)isothiazoles have been disclosed in Chemische Berichte (1964), 97(11), 3106-17.